This proposal investigates how behavioral and neurobiological responses to stressors are altered in individuals addicted to cocaine. It is hypothesized that cocaine addiction is associated with an increased behavioral reactivity to stressors that is a consequence of maladaptive alterations in the responsiveness of the hypothalamic-pituitary-adrenal (HPA) axis due to disrupted adrenocorticosteroid receptor-mediated feedback inhibition. Considering the established role of stress as a determinant of drug craving and relapse, persistent behavioral hyper-reactivity to stressors could contribute to the high incidence of relapse in abstinent addicts, a major obstacle for the effective management of cocaine addiction. The core feature of the present proposal is the use of a rat self-administration (SA) model of cocaine addiction in which addiction-related changes in stress responses will be implied from differences between rats self-administering cocaine under long-access (LgA) conditions that give rise to escalating patterns of SA and increased susceptibility to cocaine-induced relapse (i.e., 10-h access to 2.0 mg/kg/inf), rats tested under short-access (ShA rats) conditions that do not produce these effects (i.e., 3-h access to a lower cocaine dose) and non-self-administering, yoked-saline controls. Stress responses in these groups will be investigated using a series of integrated behavioral, pharmacological, and molecular studies. Differences in the behavioral reponses to stressors will be assessed by examining the reinstatement of extinguished cocaine-seeking behavior by a stressor, electric footshock, "anxiety"-Iike behaviors measured in the elevated plus-maze and defensive burying paradigms, and locomotor responses to novelty. Parallel studies will examine the activation of the HPA axis by the same stressors measured as increases in hormonal secretion, mRNA expression and glucocorticoid (GR) and/or mineralocortioid (MR) receptor activation. In order to test the hypothesis that altered responsiveness of the HPA axis is the consequence of disturbances in MR and/or GR-mediated negative feedback, MR and GR mRNA and protein expression in the pituitary gland and various brain feedback sites will be measured using in situ hybridization histochemistry and Western blot analysis. Negative feedback will be further analyzed at a functional level in experiments investigating dexamethasone-induced suppression and metyrapone-induced disinhibition of the HPA axis.